Compositions and methods for enhancing active agent absorption

Abstract

Compositions and methods for enhancing the absorption of active agents across the mucosa of animal subjects are provided. Methods of administration and appropriate dosage forms are also provided.

1 . A composition, comprising:
 a) at least one active agent; and   b) an absorption enhancer having the formula:   
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein
 R 1  is linear or branched C 1 -C 12  alkyl, C 2 -C 12  alkenyl, aryl, or substituted alkyl, alkenyl, or aryl, said substituted alkyl, alkenyl, or aryl being substituted with N, O, S, or P; 
 R 2  is hydrogen, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, aryl, or cycloalkyl functional group; 
 each R 3  is independently hydrogen, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, or aryl, or substituted alkyl, alkenyl, or aryl, said substituted alkyl, alkenyl, or aryl being substituted with N, O, S, or P; 
 X is tertiary amine, quaternary amine, tertiary sulfur, carboxylate, sulfide, sulfonate, sulfenate, sulfoxide, phosphate, phosphonate, poly(ethylene glycol), saccharide, oligosaccharide, polyol, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, chitosan, or a combination thereof; 
 Z is null, O, S, NH, or NR where R is C 1  to C 6  lower alkyl, or wherein Z is joined with R 2  to form a heterocyclic ring; and 
 B is null, —CH 2 —, O, S, or NH. 
 
   
   
       2 . The composition of  claim 1 , wherein R 1  is coupled to the aromatic ring through a coupling moiety. 
   
   
       3 . The composition of  claim 2 , wherein the coupling moiety is an amide coupling moiety. 
   
   
       4 . The composition of  claim 2 , wherein the coupling moiety is an ester coupling moiety. 
   
   
       5 . The composition of  claim 2 , wherein the coupling moiety is an ether coupling moiety. 
   
   
       6 . The composition of  claim 1 , wherein B and Z are null. 
   
   
       7 . The composition of  claim 1 , wherein B and Z are both other than null. 
   
   
       8 . The composition of  claim 1 , wherein at least one of B and Z is other than null. 
   
   
       9 . The composition of  claim 1 , wherein B is null and Z is other than null. 
   
   
       10 . The composition of  claim 1 , wherein the at least one active agent is selected from the group consisting of growth hormones, growth hormone releasing hormones, interferons, cytokines, insulins, insulin-like growth factors, heparins, calcitonins, erythropoetin, granulocyte-colony stimulating factor, atrial naturetic factor, antigens, monoclonal antibodies, somatostatin; protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing hormone releasing hormone, follicle stimulating hormone, glucocerebrosidase, thrombopoietin, human granulocyte colony stimulating factor, prstaglandins, cyclosporin, vasopressin, cromolyn sodium, vancomycin, desferrioxamine, parathyroid hormone, vitamins, polyethylene glycol derivatives of these compounds, and combination thereof. 
   
   
       11 . The composition of  claim 1 , wherein the absorption enhancer has the structure: 
     
       
         
         
             
             
         
       
     
   
   
       12 . The composition of  claim 1 , wherein the absorption enhancer has the structure: 
     
       
         
         
             
             
         
       
     
   
   
       13 . The composition of  claim 1 , wherein the absorption enhancer has the structure: 
     
       
         
         
             
             
         
       
     
   
   
       14 . The composition of  claim 1 , wherein the absorption enhancer has the structure: 
     
       
         
         
             
             
         
       
     
   
   
       15 . The composition of  claim 1 , wherein the moiety containing R 1  is para on the aromatic ring with respect to the moiety containing R 2 . 
   
   
       16 . The composition of  claim 1 , wherein the moiety containing R 1  is meta on the aromatic ring with respect to the moiety containing R 2 . 
   
   
       17 . The composition of  claim 1 , further comprising an enzyme inhibitor. 
   
   
       18 . The composition of  claim 1 , wherein the active agent is selected from the group consisting of proteins, polypeptides, hormones, polysaccharides, carbohydrates, and combinations thereof. 
   
   
       19 . The composition of  claim 1 , formulated into a dosage form selected from the group consisting of tablet, capsule, lozenge, liquid solution, liquid suspension, paste, gel, cream, powder, patch, or suppository. 
   
   
       20 . The composition of  claim 19 , wherein the dosage form is a liquid solution or suspension. 
   
   
       21 . The composition of  claim 19 , wherein the dosage form is a patch. 
   
   
       22 . The composition of  claim 19 , wherein the dosage form is a suppository. 
   
   
       23 . The composition of  claim 1 , formulated in an oral dosage form. 
   
   
       24 . The composition of  claim 1 , wherein the dosage form comprises an additive selected from the group consisting of diluents, solubilizers, excipients, flavorants, taste masking agents, surfactants, buffering agents, preservatives, antioxidants, colorants, fillers, disintegrants, lubricants, glidents, plasticizers, ethanol, pore formers, propylene glycol, saccharides, polyethylene glycol, and combinations thereof. 
   
   
       25 . A method of enhancing transmucosal absorption of active agents in a subject, comprising administering a composition to the subject so that the composition comes into effective contact with a mucosal surface of the subject, said composition comprising:
 i) at least one active agent; and   ii) an absorption enhancer having the formula:   
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein
 R 1  is linear or branched C 1 -C 12  alkyl, C 1 -C 12  alkenyl, aryl, or substituted alkyl, alkenyl, or aryl, said substituted alkyl, alkenyl, or aryl being substituted with N, O, S, or P; 
 R 2  is hydrogen, C 1 -C 12  alkyl, C 1 -C 12  alkenyl, aryl, or cycloalkyl functional group; 
 R 3  can each independently be hydrogen, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, or aryl, or substituted alkyl, alkenyl, or aryl, said substituted alkyl, alkenyl, or aryl being substituted with N, O, S, or P; 
 X is tertiary amine, quaternary amine, tertiary sulfur, carboxylate, sulfide, sulfonate, sulfenate, sulfoxide, phosphate, phosphonate, poly(ethylene glycol), saccharide, oligosaccharide, polyol, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, chitosan, or a combination thereof; 
 Z is null, O, S, NH, or NR where R is lower alkyl, or wherein Z is joined with R 2  to form a heterocyclic ring; and 
 B is null, —CH 2 —, O, S, or NH. 
 
   
   
       26 . The method of  claim 25 , wherein the mucosal surface is selected from the group consisting of buccal, sublingual, nasal, rectal, pulmonary, ocular, or vaginal. 
   
   
       27 . The method of  claim 25 , wherein the composition is administered vaginally. 
   
   
       28 . The method of  claim 25 , wherein the composition is administered rectally. 
   
   
       29 . The method of  claim 25 , wherein the composition is administered nasally. 
   
   
       30 . The method of  claim 25 , wherein the composition is administered orally. 
   
   
       31 . The method of  claim 30 , wherein the active agent is absorbed through the duodenum, ileum, or jejunum. 
   
   
       32 . The method of  claim 30 , wherein the composition is administered in a dosage form selected from the group consisting of tablet, capsule, powder, elixir, and suspension. 
   
   
       33 . The method of  claim 32 , wherein the dosage form is a liquid solution or suspension. 
   
   
       34 . The method of  claim 32 , wherein the dosage form is a tablet or capsule.